Integrative analysis of causal associations between neurodegenerative diseases and colorectal cancer

Background Observational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases. Methods Mendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results. Results Genetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127–1.1136, P = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267–1.3153, P = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694–1.2975, P = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings. Conclusions Our study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.


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Figure S1 (A) Forest plot of AD on CRC for MR analysis.(B) Funnel plot of AD on CRC for MR analysis.(C) Leave-one-out sensitivity analysis plot of AD on CRC for MR analysis.(D) Forest plot of CRC on AD for MR analysis.(E) Funnel plot of CRC on AD for MR analysis.(F) Leave-one-out sensitivity analysis plot of CRC on AD for MR analysis.

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Figure S2 (A) Forest plot of PD on CRC for MR analysis.(B) Funnel plot of PD on CRC for MR analysis.(C) Leave-one-out sensitivity analysis plot of PD on CRC for MR analysis.(D) Forest plot of CRC on PD for MR analysis.(E) Funnel plot of CRC on PD for MR analysis.(F) Leave-one-out sensitivity analysis plot of CRC on PD for MR analysis.

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Figure S3 (A) Forest plot of ALS on CRC for MR analysis.(B) Funnel plot of ALS on CRC for MR analysis.(C) Leave-one-out sensitivity analysis plot of ALS on CRC for MR analysis.(D) Forest plot of CRC on ALS for MR analysis.(E) Funnel plot of CRC on ALS for MR

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Figure S4 (A) Forest plot of LBD on CRC for MR analysis.(B) Funnel plot of LBD on CRC for MR analysis.(C) Leave-one-out sensitivity analysis plot of LBD on CRC for MR analysis.(D) Forest plot of CRC on LBD for MR analysis.(E) Funnel plot of CRC on LBD for MR analysis.(F) Leave-one-out sensitivity analysis plot of CRC on LBD for MR analysis.

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Figure S5 (A) Forest plot of FTD on CRC for MR analysis.(B) Funnel plot of FTD on CRC

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Figure S6 (A) Forest plot of AD on colon cancer for MR analysis.(B) Funnel plot of AD on colon cancer for MR analysis.(C) Leave-one-out sensitivity analysis plot of AD on colon cancer for MR analysis.(D) Forest plot of AD on rectum cancer for MR analysis.(E) Funnel plot of AD on rectum cancer for MR analysis.(F) Leave-one-out sensitivity analysis plot of AD on rectum cancer for MR analysis.

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Figure S7 (A) Forest plot of PD on colon cancer for MR analysis.(B) Funnel plot of PD on colon cancer for MR analysis.(C) Leave-one-out sensitivity analysis plot of PD on colon cancer for MR analysis.(D) Forest plot of PD on rectum cancer for MR analysis.(E) Funnel plot of PD on rectum cancer for MR analysis.(F) Leave-one-out sensitivity analysis plot of PD on rectum cancer for MR analysis.

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Figure S8 (A) Forest plot of ALS on colon cancer for MR analysis.(B) Funnel plot of ALS on colon cancer for MR analysis.(C) Leave-one-out sensitivity analysis plot of ALS on colon cancer for MR analysis.(D) Forest plot of ALS on rectum cancer for MR analysis.(E) Funnel plot of ALS on rectum cancer for MR analysis.(F) Leave-one-out sensitivity analysis plot of ALS on rectum cancer for MR analysis.

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Figure S9 (A) Forest plot of LBD on colon cancer for MR analysis.(B) Funnel plot of LBD on colon cancer for MR analysis.(C) Leave-one-out sensitivity analysis plot of LBD on colon cancer for MR analysis.(D) Forest plot of LBD on rectum cancer for MR analysis.(E) Funnel plot of LBD on rectum cancer for MR analysis.(F) Leave-one-out sensitivity analysis plot of LBD on rectum cancer for MR analysis.

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Figure S10 (A) Forest plot of FTD on colon cancer for MR analysis.(B) Funnel plot of FTD on colon cancer for MR analysis.(C) Leave-one-out sensitivity analysis plot of FTD on colon cancer for MR analysis.(D) Forest plot of FTD on rectum cancer for MR analysis.(E) Funnel plot of FTD on rectum cancer for MR analysis.(F) Leave-one-out sensitivity analysis plot of FTD on rectum cancer for MR analysis.

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Figure S11.(A) Regional association plots for AD and colon cancer at the chromosome 19 locus overlapping APOC1.(B) Colocalization analysis of AD and colon cancer.PP.H0 = neither AD nor colon cancer risk has a genetic association in the region, PP.H1 = only AD has a genetic association in the region, PP.H2 = only colon cancer risk has a genetic association in the region, PP.H3 = both AD and colon cancer risk are associated but have different causal variants, PP.H4= both AD and colon cancer risk are associated and share a single causal variant.